Summary
Electrophysiological effects of class III antiarrhythmic drugs (amiodarone, bretylium and sotalol) were examined in spontaneously beating and voltage-clamped rabbit sino-atrial node preparations, using a two microelectrode technique. At 10−6 mol/l these class III antiarrhythmic drugs prolonged the cycle length significantly, but did not affect the action potential duration. At high concentration (10−4 mol/l), amiodarone and sotalol prolonged the action potential duration as well as the cycle length. Sotalol 10−5 mol/l depolarized the maximum diastolic potential. Amiodarone 10−4 mol/l and bretylium 10−5 mol/l depressed the maximum rate of depolarization. At concentrations ranging from 10− to 10−4 mol/l, amiodarone induced dysrhythmia in 5 of 10 preparations and bretylium in 3 of 7 preparations, but sotalol in none of 5 preparations. In voltage-clamped sinoatrial node preparations, all the class III antiarrhythmic drugs decreased the slow inward current in a concentration-dependent manner. The steady-state outward and the hyperpolarization-activated inward currents were also reduced. Sotalol (10−5 mol/1) decreased both the outward current and the hyperpolarization-activated inward current stronger than the slow inward current. In addition, amiodarone (3 × 10−6 mol/l) depressed the inactivation curve for the slow inward current, but it did not shift the potential of half-maximum inactivation. The durgs also depressed the activation curve for the outward current in a concentration-dependent manner. However, the values of half-maximum activations were not influenced by these drugs as compared to control. These results suggest that the decreases in all three currents (the slow inward current, the outward current and the hyperpolarization-activated inward current) induced by class III antiarrhythmic drugs may be responsible for the negative chronotropic effect in rabbit sino-atrial node cells.
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References
Bacaner MB, Clay JR, Shrier A, Brochu RM (1986) Potassium channel blockade: a mechanism for suppressing ventricular fibrillation. Proc Natl Acad Sci USA 83:2223–2227
Bennet DH (1982) Acute prolongation of myocardial refractoriness by sotalol. Br Heart J 4: 521–526
Bergamaschi M, Shanks RG, Caravaggi AM, Mandelli V (1971) A comparison of the cardiovascular actions of four adrenergic \-receptor blocking agents in resting conscious dogs. Am Heart J 82:338–351
Bexton RS, Camm AJ (1982) Drugs with a class III antiarrhythmic action. Pharmacol Ther 17:315–355
Bkaily G, Payet MD, Benabderrazik M, Sauve R, Renaud J-F, Bacaner M, Sperelakis N (1988) Intracellular bretylium blocks Na+ and K+ currents in heart cell. Eur J Pharmacol 151:389–397
Campbell TJ (1987) Cellular electrophysiological effects of D- and DL-sotalol in guinea-pig sinoatrial node, atrium and ventricle and human atrium: differential tissue sensitivity. Br J Pharmacol 90:593–599
Carmeliet E (1985) Electrophysiologic and voltage clamp analysis of the effects of sotalol on isolated cardiac muscle and Purkinje fibres. J Pharmacol Exp Ther 232:817–825
Charlier R (1970) Cardiac actions in the dog of a new antagonist of adrenergic excitation which does not produce competitive blockade of adrenoceptors. Br J Pharmacol 39:668–674
Culling W, Penny WJ, Sheridan DJ (1984) Effects of sotalol on arrhythmias and electrophysiology during myocardial ischemia and reperfusion. Cardiovasc Res 18:397–404
Damiano BP, Rosen MR (1984) Effects of pacing on triggered activity induced by early afterdepolarizations. Circulation 69:1013–1025
Dangman KH, Hoffman BF (1981) In vivo and in vitro antiarrhythmic and arrhythmogenic effects of N-acetyl procainamide. J Pharmacol Exp Ther 217:851–862
El-Sherif N, Zeiler RH, Craelius W, Gough WB, Henkin R (1988) QTU prolongation and polymorphic ventricular tachyarrhythmias due to bradycardia-dependent early afterdepolarizations. Afterdepolarizations and ventricular arrhythmias. Circ Res 63:286–305
Follmer CH, Aomine M, Yeh JZ, Singer DH (1987) Amiodarone-induced block of sodium current in isolated cardiac cells. J Pharmacol Exp Ther 243:187–194
Gloor HO, Urthaler F, James TN (1983) Acute effects of amiodarone upon the canine sinus node and atrioventricular junctional region. J Clin Invest 71:1457–1466
Gough WB, El-Sherif N (1989) The differential response of normal and ischemic Purkinje fibres to clofilium, sotalol and bretylium. Cardiovasc Res 23:554–559
Goupil N, Lenfant J (1976) The effects of amiodarone on the sinus node activity of the rabbit heart. Eur J Pharmacol 39:23–31
Lathrop DA (1985) Electromechanical characterization of the effects of racemic sotalol and its optical isomers on isolated canine ventricular trabecular muscles and Purkinje strands. Can J Physiol Pharmacol 63:1506–1512
Markis JE, Koch-Weser J (1971) Characteristics and mechanism of inotropic and chronotropic actions of bretylium tosylate. J Pharmacol Exp Ther 178:94–102
McDonald TF, Trautwein W (1978) Membrane currents in cat myocardium: separation of inward and outward components. J Physiol (Lond) 274:193–216
Mason JW, Hondeghem LM, Katzung BG (1984) Block of inactivated sodium channels and of depolarization-induced automaticity in guinea pig papillary muscle by amiodarone. Circ Res 55:277–285
Nattel S, Talajic M, Quantz M, DeRoode M (1987) Frequency-dependent effects of amiodarone on atrioventricular nodal function and slow-channel action potentials: Evidence for calcium channel-blocking activity. Circulation 76:442–449
Noble D (1984) The surprising heart: A review of recent progress in cardiac electrophysiology. J Physiol (Lond) 353:1–50
Noma A, Irisawa H (1976) A time- and voltage-dependent potassium current in the rabbit sinoatrial node cell. Pflügers Arch 366:251–258
Pallandi RT, Campbell TJ (1987) Vmax of guinea-pig ventricular action potentials by amiodarone and desethylamiodarone}. Br J Pharmacol 92:97–103
Patterson E,Lucchesi BR (1983) Bretylium: a prototype for future development of antidysrhythmic agents. Am Heart J 106:426–431
Remme WJ, Van Hoogenhuyze DCA, Krauss XH, Hoffman A, Kruyssen DACM, Storm CJ (1985) Acute hemodynamic and antiischemic effects of intravenous amiodarone. Am J Cardiol 55:639–644
Roden DM, Hoffman BF (1985) Action potential prolongation and induction of abnormal automaticity by low quinidine concentrations in canine Purkinje fibres. Circ Res 56:857–867
Satoh H, Hashimoto K (1986) An electrophysiological study of amiloride on sino-atrial node cells and ventricular muscle of rabbit and dog. Naunyn-Schmiedeberg's Arch Pharmacol 333:83–90
Satoh H, Hashimoto K (1988) On electrophysiological responses to phorbol esters which stimulate protein kinase C in rabbit sinoatrial node cells. Naunyn-Schmiedeberg's Arch Pharmacol 337:308–315
Satoh H, Seyama I (1986) On the mechanism by which changes in extracellular pH affect the electrical activity of the rabbit sinoatrial node. J Physiol (Lond) 381:181–191
Schreiber G, Friedman M, Sokolovsky M (1984) Interaction of bretylium tosylate with rat cardiac muscarinic receptors. Possible pharmacological relevance to antiarrhythmic action. Circ Res 55:653–659
Schwartz A, Shen E, Morady F, Gillespie K, Scheinman K, Chatterjee K (1983) Hemodynamic effects of intravenous amiodarone in patients with depressed left ventricular function and recurrent ventricular tachycardia. Am Heart J 106:848–855
Singh BN, Vaughan Williams EM (1970) A third class of antiarrhythmic action. Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH3474. Br J Pharmacol 39:675–687
Strauss HC, Bigger T, Hoffman BF (1970) Electrophysiological and \ blocking effects of MJ 1999 on dog and rabbit cardiac tissue. Circ Res 26:661–678
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Satoh, H. Class III antiarrhythmic drugs (amiodarone, bretylium and sotalol) on action potentials and membrane currents in rabbit sino-atrial node preparations. Naunyn-Schmiedeberg's Arch Pharmacol 344, 674–681 (1991). https://doi.org/10.1007/BF00174751
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DOI: https://doi.org/10.1007/BF00174751